I have argued that the self-organization of the reductive citric acid cycle without the help of "informational" catalysts would be a near miracle. Recently, Morowitz et al. (13) have suggested that the contents of Beilstein's Handbook of Organic Chemistry (28, 29) strongly support the opposite point of view. Here I offer an alternative interpretation of the data presented by Morowitz et al. (13). Some of the points that I emphasize are mentioned in the commentary accompanying their paper (14).
The Beilstein handbook is a database of more than three million organic compounds that have been studied in adequate detail by organic chemists. The contents of the handbook do not represent a selection of organic compounds chosen at random from the set of all possible stable organic compounds up to some maximum complexity, but are strongly influenced by the interests of organic chemists. A compound is likely to appear in the handbook only if its interest at some time seemed to justify the effort needed to isolate or synthesize it. The study of molecules important in biochemistry has been from the beginning a dominant theme of organic chemistry, so any small molecule interesting to biochemists is virtually certain to appear in Beilstein.
The citric acid cycle is central to the oxidative metabolism of most living organisms. More importantly in the present context, the reductive (reverse) citric acid cycle has been proposed to provide an autocatalytic core metabolism, allowing a primitive organism to synthesize a wide range of biochemicals and precursors to biochemicals from carbon dioxide and hydrogen or some equivalent reducing agent (9, 13). In the form described by Morowitz et al. (13), the citric acid cycle involves 11 organic intermediates.
Morowitz et al. (13) draw far-reaching conclusions about the origins of life on Earth and elsewhere in the Universe from an analysis of the list of compounds in Beilstein. They are impressed that "there emerges through certain physically motivated pruning rules a small set of 153 compounds that includes all of the citric acid cycle intermediates." We have already seen that the citric acid cycle intermediates are almost obligatory entries in Beilstein, because they are important biochemicals. Their inclusion, taken alone, tells us nothing about their likely role in chemical evolution.
Should we be impressed by the pruning of the Beilstein database to 153 entries by a series of simple rules, or by the appearance of all of the citric acid cycle intermediates among those permitted by the pruning rules? The latter finding would certainly be impressive if the pruning rules had been devised without any knowledge of the structures of the citric acid cycle intermediates. However, an examination of the pruning rules suggests that they have been devised, perhaps inadvertently, to allow the inclusion of these substances and exclude many of the other entries in Beilstein. Compounds are included only if they contain no more than six carbon atoms, contain only carbon, hydrogen, and oxygen in certain composition ranges, include a "carbonyl" group, etc. Equally plausible rules that would occur to an organic chemist seem not to have been considered. Many would either exclude citric acid cycle intermediates or permit the inclusion of a much wider range of other compounds. Why restrict the number of carbon atoms to six rather than five or seven? The choice of five would have led to the exclusion of many of the citric acid intermediates, whereas the choice of seven would have led to the inclusion of a large number of unrelated compounds. Why adopt a seemingly arbitrary rule of composition that excludes the very soluble sugar glucose (C6H12O6 = 6 × CH2O) and numerous other sugars and related compounds, but includes acetic acid (C2H4O2 = 2 × CH2O)?
We see, therefore, that all of the citric acid cycle intermediates appear in Beilstein because they are important biochemicals and of interest to organic chemists, and that they are not excluded by the pruning rules because the pruning rules are formulated in a way that allows their inclusion. The only remaining observation that requires comment is the restriction of Beilstein entries satisfying the rules to 153 items. I can see three possible reasons for the relatively small number of entries. First, the pruning rules may be so restrictive that there are only a limited number of stable compounds simultaneously satisfying them and the valency rules of organic chemistry. Second, organic chemists may not be interested in many of the compounds allowed by the rules if they are not of biological significance. Third, production of many of the nonbiological compounds by the methods of synthetic organic chemistry may be difficult. The first two explanations would not permit any connection to be made with early evolution. The third, if correct, might have some relevance to prebiotic chemistry, because it would strengthen somewhat the view that the central molecules of biochemistry are likely to be molecules for which relatively simple prebiotic syntheses are available. In summary, although it seems plausible on general grounds that the reverse citric acid cycle is an early biochemical "invention," the contents of Beilstein do not provide any new evidence to support such a conclusion, or suggest that the cycle self-organized.
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